POS0093 TRANSCRIPTOMIC AND METHYLOMIC PROFILING OF CD4+ T-CELLS IN GIANT CELL ARTERITIS WITH DIFFERENT DISEASE ACTIVITY
Authors: E. Estupiñán-Moreno, J. Hernández-Rodríguez, T. LI, L. Ciudad, E. Andrés-León, L. C. Terron-Camero, S. Prieto-González, G. Espígol-Frigolé, M. C. Cid, A. Márquez, J. Martin Ibanez, E. Ballestar, L. Ortiz-Fernández
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Giant cell arteritis (GCA) is an inflammatory large-vessels vasculitis representing an important clinical challenge. First, an early diagnosis of GCA is difficult due to the clinical heterogeneity and the lack of specific biomarkers. In addition, although the therapy generally used are glucocorticoids (GC), relapses are common when GC are tapered [1]. The etiology of this disorder is complex in which multiple genetic and epigenetic factors contribute to its development [1]. Although the pathogenic mechanisms remain insufficiently understood, a central role for CD4+ T-cells has been demonstrated [2]. In this context, understanding how the transcriptome and methylome of this cell type are altered in GCA patients and how they are influenced by GC will yield new insights into the pathogenesis of this vasculitis. <h3>Objectives</h3> To shed light into GCA pathogenesis and to identify molecular mechanisms that might serve as novel biomarkers or potential drug targets, we characterized the transcriptome and methylome signatures of GCA CD4+ T-cells and the way these cells are affected by remission and by the effect of GC. <h3>Methods</h3> Both DNA and RNA were isolated from CD4+ lymphocytes positively sorted by flow cytometry from whole blood. Subsequently, DNA methylation profiling with the Illumina Infinium Methylation EPIC array and RNA-sequencing were carried out. After quality controls, epigenome- and transcriptome-wide association were performed for 81 samples: 23 healthy controls and 58 GCA patients grouped in three different clinical status (active before starting GC [n= 13], in remission with GC [n= 22], and in remission without GC [n= 23]). <h3>Results</h3> The results of this work revealed a profound dysregulation in both the gene expression and DNA methylation patterns of CD4+ T-cells of GCA patients. Particularly, CD4+ T-cells from GCA patients with an active state of the disease before starting GC treatment showed substantial changes in inflammatory processes, such as NOTCH1, interleukin-6 (IL-6), IL-1 and vitamin D receptor signalling pathways, among others. In addition, we also observed alterations in molecular pathways related with angiogenesis, the vascular endothelial growth factor (VEGF) receptor, and with the differentiation of T helper 2 (Th2), including the IL-2/STAT5 and IL-4 pathways. Interestingly, our findings also indicated that the pro-inflammatory expression profiles observed in the active disease are lost when the disease subsides, and that GC therapy significantly remodels both the transcriptome and the methylome of CD4+ T-cells. Particularly, changes in molecular mechanisms related to drug metabolism, such as GC receptor genes and glucuronosyltransferase family genes were also found. <h3>Conclusion</h3> The results of the transcriptome and methylome characterization of GCA CD4+ T-cells have provided new evidences of genes and pathways contributing to the pathogenic role of this cell type in GCA, providing a clearer picture of the molecular processes driving disease activity and how they vary in response to GC treatment. <h3>References</h3> [1]Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum. 15;61(10):1454-61. 2009. [2]Weyand, C., Goronzy, J. Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol 9, 731–740. 2013. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.